Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure.
Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure.
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发表时间：
1996-08
期刊：
影响因子：
11.2
通讯作者：
J. Issa;S. Baylin;S. Belinsky
中科院分区：
文献类型：
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作者：
J. Issa;S. Baylin;S. Belinsky
启动子甲基化最近被证明是一种替代突变失活肿瘤抑制基因在人类肿瘤。虽然特定的致癌物暴露与基因的特征突变模式有关，但导致启动子高甲基化的因素仍然未知。通过启动子甲基化失活的一个基因靶标是雌激素受体（ER）。本研究的目的是确定吸烟者和从不吸烟者以及暴露于特定环境致癌物的啮齿动物的肺肿瘤中该基因的甲基化状态。在11例从不吸烟者的肿瘤中有4例（36.4%）和35例吸烟者的肿瘤中有7例（20%，P < 0.001）检测到ER基因启动子甲基化。烟草致癌物4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮诱导的肺肿瘤也有较低的ER甲基化发生率（16.7%）。与此形成鲜明对比的是，自发性肿瘤和钚诱导的肿瘤ER甲基化的发生率非常高（81.8%）。X射线诱导的肿瘤有中等频率的ER甲基化（38.1%）。在啮齿动物肺癌细胞系中，ER甲基化的存在与ER表达的缺失相关。这些结果首次表明，基因特异性启动子甲基化可以根据致癌物暴露差异调制。
Promoter methylation has recently been shown to be an alternative to mutation in inactivating tumor suppressor genes in human neoplasia. Although specific carcinogen exposures have been associated with characteristic mutation patterns in genes, the factors that lead to promoter hypermethylation remain unknown. One gene target for inactivation through promoter methylation is the estrogen receptor (ER). The purpose of this investigation was to determine the methylation status of this gene in lung tumors from smokers and those who never smoked and in rodents exposed to specific environmental carcinogens. Promoter methylation at the ER locus was detected in 4 of 11 tumors from never-smokers (36.4%) and 7 of 35 tumors from smokers (20%, P < 0.001). Lung tumors induced by the tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone also had a low incidence (16.7%) of ER methylation. In marked contrast, spontaneous and plutonium-induced tumors had a very high (81.8%) incidence of ER methylation. X-ray-induced tumors had an intermediate frequency of ER methylation (38.1%). The presence of ER methylation was associated with absent ER expression in rodent lung cancer cell lines. These results show for the first time that gene-specific promoter methylation can be modulated differentially depending on carcinogen exposure.